5-Fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (Emtricitabine) is used as an antiviral drug. Emtricitabine is marketed under the trade name Emtriva. Emtricitabine is the (−) enantiomer of a thio analogs differing from other cytosine analogs viz. Lamivudine in that it has a fluorine in the 5-position.
There are various processes used in the prior art for preparation of Emtricitabine using different synthetic routes.
WO 92/14743 discloses the racemic mixture of cis isomers, which are prepared using standard reactions followed by resolution employing enzymatic methods to yield 2R, 5S enantiomer.
Stereoselective synthetic routes were subsequently developed, which by means of the use of chiral auxiliaries such as menthol, allow the desired stereochemistry to be induced and allow Emtricitabine to be obtained directly as single enantiomer. U.S. Pat. No. 5,696,254 illustrates stereoselective synthesis approach for synthesis of Emtricitabine, as shown below:

In the above scheme the trans oxathiolane is prepared (Step 1, VIII) which, when acetylated (Step 2, IX) and condensed with 1-menthol, leads to the mixture of intermediate diastereoisomers (Step 3, X). The desired diastereomer is isolated by fractional crystallization (Step 4) and coupled with silylated 5-fluorocytosine (III) (Step 5), leading to the derivative XI which finally by reductive removal of the chiral auxiliary (Step 6) gives Emtricitabine.
U.S. Pat. No. 6,051,709 describes a stereoselective process for the synthesis of cis nucleosides, this process differing from the above process essentially by the use of leaving groups other than acetate such as halo, cyano or sulphonate in the coupling reaction of the intermediate X with the activated 5-fluorocytosine III.
However, the experimental illustration is limited to the preparation of the non-fluoro analogue of Emtricitabine, known as Lamivudine (as illustrated in scheme 1, columns 9-10), without any indication regarding the actual process yields. Example 1 describes the preparation of 5-hydroxyoxathiolane required by reacting 1-menthyl glyoxalate and dithianediol (part a, column 10), and the subsequent formation of the chloro derivative (part b, column 10) and its coupling reaction with cytosine silylate (last paragraph, column 10, first paragraph, column 11). The resulting product, which precipitates from the reaction medium, is recovered by simple filtration and subjected to reductive removal of the chiral auxiliary to give the crude Lamivudine, which is purified, not by direct crystallization of the base but of the salified form, in particular of the salicylate. It is obvious that, by this procedure, a subsequent basic treatment will be necessary to release the lamivudine base from its salt. This procedure, which does not appear to present any particular implementation difficulties in the case of Lamivudine, becomes entirely inapplicable when used for the preparation of Emtricitabine.
U.S. Pat. No. 5,728,575 disclose a method to obtain Lamivudine and Emtricitabine via enzymatic resolution of the 5′-acyl protected racemic nucleoside using pig liver esterase, porcine pancreatic lipase, or subtilisin.
U.S. Pat. No. 5,827,727 disclose a method to obtain Lamivudine and Emtricitabine via stereoselective deamination using cytidine deaminase.
U.S. Pat. No. 5,892,025 disclose a method for the resolution of the combination of the enantiomers of cis-Emtricitabine by passing the cis-Emtricitabine through an acetylated β-cyclodextrin chiral column.
The present invention provides an alternative process stereo-selective preparation of Emtricitabine, which is commercially viable and allows the desired product, to be obtained in good yield.